Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

J Biol Chem. 2016 Jan 1;291(1):402-12. doi: 10.1074/jbc.M115.666347. Epub 2015 Oct 20.


Histone lysine methylation is important in early zebrafish development; however, the role of histone arginine methylation in this process remains unclear. H3R2me2a, generated by protein arginine methyltransferase 6 (Prmt6), is a repressive mark. To explore the role of Prmt6 and H3R2me2a during zebrafish embryogenesis, we identified the maternal characteristic of prmt6 and designed two prmt6-specific morpholino-oligos (MOs) to study its importance in early development, application of which led to early epiboly defects and significantly reduced the level of H3R2me2a marks. prmt6 mRNA could rescue the epiboly defects and the H3R2me2a reduction in the prmt6 morphants. Functionally, microarray data demonstrated that growth arrest and DNA damage-inducible, α, a (gadd45αa) was a significantly up-regulated gene in MO-treated embryos, the activity of which was linked to the activation of the p38/JNK pathway and apoptosis. Importantly, gadd45αa MO and p38/JNK inhibitors could partially rescue the defect of prmt6 morphants, the downstream targets of Prmt6, and the apoptosis ratios of the prmt6 morphants. Moreover, the results of ChIP quantitative real time PCR and luciferase reporter assay indicated that gadd45αa is a repressive target of Prmt6. Taken together, these results suggest that maternal Prmt6 is essential to early zebrafish development by directly repressing gadd45αa.

Keywords: apoptosis; c-Jun N-terminal kinase (JNK); gadd45αa; histone methylation; p38; prmt6; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Embryonic Development* / drug effects
  • Embryonic Development* / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Morpholinos / pharmacology
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein-Arginine N-Methyltransferases / genetics*
  • Protein-Arginine N-Methyltransferases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stress, Physiological / drug effects
  • Stress, Physiological / genetics
  • Up-Regulation / drug effects
  • Zebrafish / embryology*
  • Zebrafish / genetics*
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cell Cycle Proteins
  • Morpholinos
  • Nuclear Proteins
  • RNA, Messenger
  • Zebrafish Proteins
  • gadd45aa protein, zebrafish
  • Prmt6 protein, zebrafish
  • Protein-Arginine N-Methyltransferases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases